The human brain is composed of a complex neural network of various types of neurons. Various neurotransmitters-mediated signaling pathways regulate neuronal activity in brain. PLCγ1 is highly expressed in forebrain and participates in diverse neuronal functions including neurite outgrowth, migration, and synaptic plasticity in human brain. Recently, many studies reported that impairment of the PLCγ1-mediated signaling pathway appears to be causally linked to various brain disorder such as depression, epilepsy and bipolar disorder. However, previous in vitro studies have limitations that cannot be verified in vivo because PLCγ1 null mouse exhibits embryonic lethality. Therefore, we generated the PLCγ1 conditional knockout mouse to identify the neuronal cell type-specific function of PLCγ1 and pathophysiological mechanism of brain disorder.

 

The imbalance between excitation and inhibition across neurons is a major cause of neurological disorders.  In brain, GABAergic neurons (inhibitory neurons) and pyramidal neurons (excitatory neurons) are known to communicate with each other to maintain excitatory/inhibitory (E/I) balance. In this context, the disruption of E/I balance by dysregulation of signal transduction could lead to abnormal hyperexcitability, contributing to bipolar disorder and epilepsy. However, the molecular mechanism underlying dysregulation of E/I balance has not been clearly defined yet. To identify the neuron type-specific roles of PLCγ1 for E/I regulation, we generated Plcg1f/f; CamKⅡ-cre mice for excitatory neuron-specific Plcg1 gene deletion and Plcg1f/f; Dlx5/6-cre mice for GABAergic neuron-specific Plcg1 gene deletion. We found that forebrain-specific deletion of PLCγ1 exhibit manic-like behavior because of dysfunction of inhibitory synapse in Plcg1f/f; CamKⅡ-cre mice(Yang et al., 2007). Also, we are going to study the role of PLCγ1 in GABAergic neuron with Plcg1f/f; Dlx5/6-cre mice. We suggest that PLCγ1 signaling in GABAergic neuron could prevent hyperexcitability by regulating GABAergic synaptic function.